While the problem of female infertility has been a focus of scientific political, and media attention, abnormalities in the male account for 30- 50% of all infertile cases, yet has received little attention. Most cases of male infertility are a consequence of too few or abnormal sperm, yet the factors that contribute to the problem are unknown. As a result, relative little effective therapy has been established for the male with impaired sperm production. The development of intracytoplasmic sperm injection (ICSI) with in vitro fertilization (IVF) has improve our ability to use suboptimal semen specimens to produce conceptions. ICSI has been used to achieve pregnancies for patients with genetic causes of infertility and for axoospermic patients with severe spermatogenic defects by testicular sperm extraction (TESE). It is likely that many types of "idiopathic" infertility are actually due to genetic defects. In this translational project, we will test the hypothesis that genetic instability is present in the testis of some axospermic candidates for TESE-ICSI. This will be examined at the constitutional chromosomal level using high resolution banding cytogenetics and fluorescent in situ hybridization (FISH) and at the level of specific nucleotides using microsatellite instability and Y chromosome deletion intervals. We propose to evaluate the safety of game micromanipulation in human IVF. Clinical and genetic assessment of each subfertile man and long-term genetic and developmental ealaut8ion of the children resulting from micromanipulation will be performed. The results of these studies will be evaluated in association with state-of-the- art clinical and molecular laboratory examination of the male that is necessary for proper patient classification. We propose that molecular characterization of patients may provide the most important insights into ICSI outcomes. Finally, we will use neural computation to model ICSI outcomes derived from this proposal. Our long-range goal is to develop a safe and effective treatment for the infertile male patient.